Oral clonidine and gabapentin suppress pressor response: A prospective, randomized, double blind study.

BACKGROUND: Pressor response is a part of stress response caused by reflex sympathetic discharge due to direct laryngoscopy and tracheal intubation resulting in tachycardia, hypertension and arrhythmias. Both clonidine, and gabapentin administered orally can effectively blunt this detrimental hemodynamic response. AIM: To study the effect of oral clonidine to blunt the pressor response to direct laryngoscopy and to compare it with oral gabapentin. To observe for postoperative sedation and side effects if any. SETTINGS AND
DESIGN: Sixty patients of American Society of Anaesthesiologist Grade I and II scheduled for surgery under general anesthesia were considered in this prospective randomized double-blind study. They were randomly allocated into two groups of 30 each using computerized randomization.
MATERIALS AND METHODS: Group A was given oral clonidine 5 μg/kg and Group B was given oral gabapentin 800 mg. Both the drugs were given 90 min prior to surgery. Heart rate (HR) and blood pressure were monitored at baseline, 0, 1, 3, 5, 10, 15, and 30(th) min of laryngoscopy. Sedation was monitored by Ramsay Sedation Scale score and side effects were noted.
RESULTS: HR decreased in both groups at 0 and 1 min, increased at 3(rd) min and gradually decreased by 30(th) min. Statistically, significant difference was found between two groups at 1, 3, 5, 10, and 15(th) min (P < 0.05). Though there was no significant difference in systolic blood pressure, diastolic blood pressure and mean arterial pressure between the two groups, there was no rise in these parameters. Gabapentin produced more sedation than clonidine postoperatively, and few side effects were noted.
CONCLUSION: Both oral clonidine and gabapentin are effective in obtunding pressor response to direct laryngoscopy, clonidine being better in terms of controlling HR. Gabapentin produces more postoperative sedation than clonidine.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

The stress response is the name given to the hormonal and metabolic changes which follow injury or trauma.[1] The pressor response is a part of the stress response associated with hemodynamic changes due to reflex sympathetic discharge caused by direct laryngoscopy and tracheal intubation. This increased sympathoadrenal activity may result in hypertension, tachycardia and arrhythmias.[234]

Transient hypertension and tachycardia are probably of no consequence in healthy individuals, but either or both may be hazardous to those with hypertension, myocardial insufficiency and cerebrovascular diseases which are common occurrences in elderly individuals.[567] At least in such individuals there is a necessity to blunt this response.

Anesthesiologists have been trying a variety of drugs from their armamentarium to suppress this notorious “pressor response.” Drugs which can be used to control this hemodynamic response include vasodilators, beta blockers, calcium channel blockers, α2-agonists, lignocaine, and opioids. However, no modality is devoid of drawbacks and limitations.

Clonidine is a α2A-adrenergic agonist which decreases central sympathetic outflow and reduces blood pressure by an effect on both cardiac output and peripheral resistance. It tends to attenuate stress response to surgical stimulus, direct laryngoscopy and improves overall perianesthetic stability.

Gabapentin, a relatively new drug was introduced as antiepileptic, but proved to be effective in controlling neuropathic pain. Gabapentin has been used to treat acute postoperative pain and also to decrease postoperative opioid requirements.[89]

More recently, it has been used to attenuate the pressor response to direct laryngoscopy and tracheal intubation.[10111213]

A basic need is continuously felt among the anesthesiologist fraternity for the desired availability of a drug that effectively suppresses the hazardous responses to obnoxious stimuli with a maximum safety margin. Hence, we designed a randomized prospective double-blinded study to evaluate the effectiveness of oral clonidine premedication on attenuation of the hemodynamic response to direct laryngoscopy and compared it with oral gabapentin.

MATERIALS AND METHODS

This study was a prospective, randomized, double-blind, single center study. The study was conducted in a Tertiary Care Level Institute and a Clinical Research Organization after Ethical Committee approval. A total of 60 patients of American Society of Anaesthesiologist physical status (ASA) Grade I and II, age between 15 and 65 years of both sexes were studied. Patients with co-morbid conditions such as hypertension, diabetes, renal or hepatic disease and pregnancy were excluded. Furthermore, patients on antihypertensive medication and those with anticipated difficult airway were excluded. Patients were randomly allocated to one of two groups by allocation sequence generated by computer-generated random number table. Each group consisting of 30 patients. Group allocation was done by an anesthesiologist who was not the part of study design. Drugs were administered by the anesthesiologist who was not the part of data collection and analysis. Group A received oral clonidine 5 µg/kg and Group B received oral gabapentin 800 mg, 90 min prior to surgery with sips of water.

In the operating room, intravenous (i.v.) cannula was secured, and standard monitors were placed.

Monitoring included heart rate (HR), electrocardiogram, noninvasive blood pressure, pulse oximetry (SpO2) and end tidal CO2 (ETCO2). Baseline (preinduction) HR, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) of the patients were noted. After preoxygenation, all patients were induced with injection propofol (2 mg/kg) i.v. and injection suxamethonium (2 mg/kg) i.v.

After the introduction of direct laryngoscope HR, SBP, DBP and MAP were monitored at 0, 1, 3, 5, 10, 15, and 30 min of laryngoscopy. Baseline reading was taken after giving clonidine or gabapentin orally. 0th min reading indicates values after induction and before intubation. The rest of the readings were taken after intubation.

Intubation was done with the appropriate sized endotracheal tube. Intubation was done by trained anesthesiologists in all cases. Duration of laryngoscopy and intubation was restricted to <30 seconds as measured by a stopwatch. In case of hypotension mephentermine, 6 mg i.v. and for bradycardia atropine 0.6 mg i.v. was kept as a rescue treatment. However, none of the patients required above clinical intervention. Postoperative sedation was evaluated using Ramsay Sedation Scale score, and side effects of these drugs were noted.

Statistics

Preliminary sample size estimation showed that approximately 30 patients should be included in each group. It was assumed that 15% reduction in HR and blood pressure will be clinically meaningful with estimated standard deviation of 11 for HR and 20 for blood pressure respectively, in order to ensure the power of 80%. An alpha error was assumed to be 0.05 (95% confidence interval).

Patient characteristics were compared using two independent sample t-test and Chi-square test. HR, SBP, DBP and MAP were compared using two independent sample t-test. Sedation score was compared using Mann–Whitney U-test. P < 0.05 was considered significant, P > 0.05 not significant and P < 0.001 highly significant. Data analysis was done using Statistical Package for Social Science (SPSS) version 17.0 (SPSS Inc., Chicago II, USA).

RESULTS

Demographic data when analyzed did not show any significant difference in age, weight, height, and sex ratio among two groups and thus the two groups were comparable as shown in Table 1.

Table 1

Demographic data

The mean values of pulse rate and MAP are shown in Tables 2 and 3, respectively, and these are represented graphically in Figures 1 and 2, respectively. It can be seen that, there was a decrease in pulse rate in both groups at 0th and 1st min, it increased at 3rd min and gradually decreased by 30th min. Pulse rate was better controlled in Group A at all times than Group B and it was statistically significant at 1 min (P = 0.001), 3 min (P = 0.018), 5 min (P = 0.014), 10 min (P = 0.006) and 15th min (P = 0.006).

Table 2

Comparison of mean pulse rate in Group A and Group B

Table 3

Comparison of MAP in Group A and Group B

Figure 1

Comparison of mean pulse rate in Group A and Group B

Figure 2

Comparison of mean arterial pressure

Similarly, MAP was decreased in both groups than baseline at all times except at 3rd min. Although the fall appears to be more in Group A as compared to Group B, no statistically significant difference was noted between the two groups except at 15 min (P = 0.012) and 30th min (P < 0.001) [Table 3 and Figure 2].

Furthermore, there was fall in SBP and DBP in both groups as compared to baseline at all times except at 3rd min. The difference was not statistically significant (P > 0.05) [Table 4 and Figure 3].

Table 4

Comparison of SBP in Group A and Group B

Figure 3

Comparison of mean systolic blood pressure

In Group A, number of patients with Ramsay Sedation Scale score of 1 and 2 were 22 and 8, respectively. The number of patients in Group B with a sedation score of 1 and 2 were 13 and 16, respectively. One patient in Group B has sedation score of 3. Statistically, a significant difference is noted between the two groups in the postoperative sedation score. (P = 0.017) [Table 5 and Figure 4].

Table 5

Comparison of sedation score between Group A and Group B

Figure 4

Comparison of sedation score

Side effects pertaining to clonidine and gabapentin were noted. In Group A, 8 patients had dry mouth, and 4 patients showed bradycardia. In Group B, 8 patients complained of drowsiness.

DISCUSSION

Achievement of smooth induction with the minimal hemodynamic stress response to direct laryngoscopy is an important anesthetic goal. Direct laryngoscopy and tracheal intubation is routinely performed during the administration of general anesthesia. This pressor response causes tachycardia, hypertension, and increased the workload on the myocardium and its subsequent detrimental effects. Several pharmacological agents have been tried to decrease this response in past.

Both clonidine and gabapentin are being investigated as useful adjuncts to anesthesia. Clonidine has known sedative, analgesic, and anxiolytic properties. It stimulates α2-adrenergic inhibitory neurons in the medullary vasomotor center. Decreased central sympathetic outflow is manifested as peripheral vasodilatation and decrease in systemic blood pressure, HR and cardiac output. One of the highest densities of α2-receptors is present in pontine locus ceruleus, a vital modulator of vigilance. Sedative effects of clonidine reflect inhibition of this nucleus.

Gabapentin, a structural analog of neurotransmitter gamma amino butyric acid acts by inhibiting calcium influx and subsequent release of excitatory neurotransmitter in pain pathways by binding to α2 subunit of the presynaptic voltage-gated Ca2+ channels. Gabapentin is a second-generation anticonvulsant that is, effective in the treatment of chronic neuropathic pain. It was shown to be effective in treating a variety of chronic pain conditions, including postherpetic neuralgia, diabetic neuropathy, complex regional pain syndrome, inflammatory pain, central pain, malignant pain, trigeminal neuralgia, HIV-related neuropathy, and headaches. The mechanism by which gabapentin attenuates the pressor response to laryngoscopy and intubation is unknown. The drug inhibits membrane voltage-gated calcium channels, thus acting in a manner similar to calcium channel blockers and calcium channel blockers have been found to be effective in blunting the pressor response, so that may be the underlying mechanism of action.

Fassoulaki et al. have shown the efficacy of gabapentin in attenuating the pressor response. 100 patients undergoing elective surgery were randomly allocated into two groups of 50 patients each. Patients in Group A received gabapentin 800 mg and patients in Group B received placebo capsules the night before and on the morning of surgery.[11] SBP was significantly lower in the gabapentin as compared to the control group 0, 1, 3, 5, and 10 min after intubation. DBP also was lower in the gabapentin group 0, 1, 3, and 5 min after intubation. MAP also was lower in the gabapentin group 0, 1, 3, and 5 min after intubation. HR also was lower in the gabapentin group 0, 1, and 3 min after intubation.

In our study, demographic data, when analyzed, did not show any significant difference in age, weight, height and sex ratio among two groups, and thus the two groups were comparable.

The hemodynamic pressor response to direct laryngoscopy and intubation as observed by change in pulse rate, SBP, DBP, and MAP were attenuated in both groups, effect being more significant in Group A to control pulse rate. Both drugs were equally effective to control SBP, DBP and MAP.

Singhal et al. conducted a similar study. They allocated 100 patients into two groups of 50 each. Group A received oral clonidine 200 µg and Group B received oral gabapentin 900 mg 90 min prior to surgery. The study revealed that rise in HR was obtunded in group A as compared to Group B except at 1st min. MAP values were found below baseline at all times in Group A as compared to Group B in which significant rise was seen at 1st min. The results are similar to our study.[12]

In another study, Marashi et al. concluded with contrasting results. They investigated the comparative assessment of clonidine and gabapentin premedication on attenuation of hemodynamic responses following laryngoscopy and tracheal intubation.[13] Group I received 0.2 mg clonidine, Group II received placebo, and Group III received 900 mg gabapentin, 120 min before the operation. The analysis revealed that the HR, systolic, diastolic and mean arterial blood pressure significantly differed between groups. The highest rates of HR, systolic, diastolic, and mean arterial blood pressure were in the placebo group and the lowest rate were in the gabapentin group at the time of 1, 3, 5 min of laryngoscopy, except that the lowest rate of HR in 10 min after laryngoscopy was in clonidine group.

Montazeri et al. conducted a study on 96 patients. These were divided into three groups of 32 each. Group P received placebo; Group G was given gabapentin 800 mg and Group C clonidine 0.3 mg. The analysis revealed HR significantly reduced in Group G and Group C as compared to Group P just before laryngoscopy. No significant difference was noted between Group G and Group C with respect to variables SBP, DBP, MAP. The results are similar to our study.[14]

Memis et al. studied 90 normotensive patients (ASA Grade I) undergoing elective surgery. They were divided into three groups of 30 patients each. Patients received oral placebo (Group I), 400 mg of gabapentin (Group II) or 800 mg of gabapentin (Group III) 1 h prior to surgery in the operating theatre. The HR and arterial pressure was significantly less in Group III at 1, 3, 5 and 10 min after intubation compared to Groups I and II.[10]

Shreedhara et al. compared gabapentin and clonidine for a pressor response with similar results.[15] However, they did not compare the sedation with the two drugs. The postoperative sedation, as observed by Ramsay Sedation Scale score was more in gabapentin as compared with clonidine.

Clonidine and gabapentin have certain adverse effects inherent to their structure. Clonidine can cause dry mouth, sedation, hypotension and marked bradycardia. The most frequent side-effects reported with gabapentin are somnolence, dizziness, ataxia, fatigue, unsteadiness, nystagmus, headache, tremors, diplopia, and nausea. Few side effects such as sedation, bradycardia in Group A and drowsiness in Group B were observed. None of these side effects warranted any active clinical intervention. However, this single dose use of these drugs is unlikely to cause above effects.

Propofol was used for induction in both groups in our study; it can interfere with the assessment of pressor response as it can cause bradycardia and hypotension. However, it was used in both groups. Other inducing agents like thiopentone may cause tachycardia and may reveal misleading results. We did not measure levels of catecholamine during the study. These can be considered limitations of our study.

Hemodynamic pressor response is a complex process that is affected by multiple factors including depth of anesthesia, opioid use in premedication, i.v. anesthetics, inhalational agents and use of supraglottic airway devices to name a few. Future studies can be directed toward the effect of these confounding factors on the efficacy of clonidine and gabapentin. These can be supplemented by concurrent measurement of catecholamine and cortisol levels for better correlation.

CONCLUSION

Overall, we conclude that both oral clonidine 5 µg/kg and oral gabapentin 800 mg given as premedication 90 min prior to surgery, effectively attenuates hemodynamic pressor response to direct laryngoscopy. Clonidine controls pulse rate better than gabapentin whereas both drugs equally reduces blood pressure. Gabapentin produces more postoperative sedation than clonidine. Few side effects like dry mouth and bradycardia with clonidine and drowsiness with gabapentin were noted requiring no active clinical intervention.

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Nil.

Conflicts of interest

There are no conflicts of interest